This multidisciplinary application supports a strategy of combining patient-oriented research with the science based investigation of disease causation. The overall aim is to understand the mechanisms that apparently protect the oral epithelium from HIV infection. The long-term objective is to understand the basis of copathogenicity in the immunocompromised host leading to the delivery of more effective therapies. We hypothesize that HIV directly affects the oral epithelial proteome, leading to alterations that promote colonization and infection of the co-pathogen Candida. The specific aims are: 1) To fully characterize the constituents of the oral epithelium that protects the oral mucosa from HIV and Candida infection. Using oral and vaginal epithelial models, and human and macaque samples, the canonical receptors for both HIV and Candida will be investigated by flow cytometry. The epithelial proteome in the presence or absence of HIV and Candida will be then be fully characterized in order to identify protective or susceptibility factors to HIV and Candida infection in these mucosae. Saliva will be applied to the models to investigate the contribution of innate secretory factors present in oral fluids that may inhibit HIV or Candida infection Transcript profiling, quantitative RT-PCR, and Luminex protein assays will be performed to support the proteomic data. 2) To characterize the innate TLR-associated proteomic response elicited by human epithelium during HIV and Candida infection. The HIV- and C. a/b/cans-induced epithelial cytokine, chemokine, TLR1-10 and signaling pathway expression profiles will first be characterized in oral and vaginal epithelial models using proteomics. The PMN-dependent TLR-mediated protection mechanism against oral C. albicans infection will then be fully characterized using transcript profiling, real-time RT-PCR, confocal and immunoelectron microscopy, and siRNAi. Relevance: HIV/AIDS is most commonly transmitted through mucosal membranes. In some circumstances, the oral tissues are exposed to HIV but rarely become infected. Understanding the mechanism by which the oral cavity is apparently protected from infection could lead to the development of therapies to protect other mucosal tissues such as the vagina from infection and transmission of the virus. This could also lead to therapies for the treatment of the co-infections associated with HIV such as oral Thrush.